European Journal of Clinical Nutrition (2012) 66, 979–982 & 2012 Macmillan Publishers Limited All rights reserved 0954-3007/12 www.nature.com/ejcn

EDITORIAL Mechanisms and implications of bone adipose tissue-mineral relationships

European Journal of Clinical Nutrition (2012) 66, 979–982; marrow and 1.5 kg yellow marrow (1.3 kg of each in the reference 15 doi:10.1038/ejcn.2012.88 58 kg female).

INVERSE BONE MINERAL AND BONE FAT RELATIONSHIP BACKGROUND Since fat accumulates in bone marrow, while mineral is lost Although there has been extensive interest in the adverse effects especially after age 30–40 years, an inverse relationship between of obesity on health and the role of fat distribution between and individuals of widely different adult ages is expected to exist, and many scanning studies support the information obtained from within different tissues, the significance of fat in the bone marrow 15,16 has received relatively little attention. This issue of European bone biopsy or autopsy studies. However, it is more difficult to Journal of Clinical Nutrition contains an article1 that reports an conclude that the same inverse relationship applies to individuals inverse relationship between intra-osseous adipose tissue volume, of comparable age, especially since several studies examining measured in the pelvis of adults using magnetic resonance bone adipose tissue (or fat)-mineral relationships have not adjusted for age.16,17,19–22 A few studies have adjusted for imaging (MRI), and bone mineral density (BMD) of the pelvis, 23,24 1 lumbar vertebrae and the whole body, measured using dual age, among them being the recent study of Shen et al. This energy X-ray absorptiometry (DXA). They suggest that the two last study stands out from others in that it has substantial power may be causally linked according to an existing hypothesis about due to the large sample size (200 aged 18–40 years and another mesenchymal stem cells, which can preferentially differentiate 200 440 years) and in demonstrating that the inverse bone into adipocytes or osteoblasts. The paper not only raises questions adipose tissue-mineral relationship is robust, persisting in both the about the biology of mineralisation and fat metabolism in bone, younger and older groups even after adjustment for multiple but also about the potential interaction between them and their variables (age, weight, total body fat, subcutaneous adipose tissue, relevance to the development of osteoporosis. To contextualise visceral adipose tissue, skeletal muscle, sex, ethnicity and the new findings, it is helpful to first briefly consider the normal menopausal status; r values ranging from À 0.155 and À 0.266). changes in both the fat and mineral content of bone which occur The paper raises questions about the mechanisms responsible for during the normal adult lifespan. the inverse bone adipose tissue-mineral relationship and the There has been some controversy about the age of peak bone merits and limitations of different methodological approaches to mass using measurements of whole body BMD or bone mineral assess such relationships. content (BMC) obtained by DXA. Some studies indicate that it occurs at 20–30 years2,3 (longitudinal and cross-sectional studies), but others suggest that it occurs later at 30–40 years4,5 and POSSIBLE MECHANISMS RESPONSIBLE FOR THE INVERSE perhaps earlier in the late teens.6,7 The age varies according to BONE MINERAL-FAT RELATIONSHIP gender, ethnicity, pubertal status, physical activity and genetic A key hypothesis supported by Shen et al.1 concerns mesangial factors. It also varies according to the type of bone8–10 and even stem cells that can differentiate into either osteoblasts or fat region within the same bone.8–10 Peak bone mass of the lumbar cells.25 Preferential differentiation into osteoblasts can help spine has generally been reported to occur at 20–40 years8–14 but explain why more bone is associated with less fat, and vice at the femoral neck, it has often been reported to occur earlier at versa. The hypothesis, which is based on experimental laboratory around 20 years or even earlier.8–10 There appears to be little work, is attractive because it is conceptually simple, with a single information about age of the peak bone mass of the pelvis. In the event explaining partitioning of tissue into fat and bone. However, whole body little net bone loss generally occurs before the age of a number of alternative hypotheses can also be suggested. For 40 years, although about a 10% reduction in BMD has been example, a traditional explanation is that fat simply accumulates reported to occur at some sites.8,10 passively in the variable bone marrow space26 made available The temporal pattern of change in bone fat differs from that of during development and remodelling. However, this does not mineral in that it continues to accumulate in bone during the explain why the marrow space is not filled by extracellular fluid or entire lifespan15–17 due to two major processes. First, red marrow another type of tissue/substance. Another hypothesis is that the (a homeopoietic tissue), which contains a smaller proportion of fat, biological variation in bone to marrow space, known to occur both is replaced by yellow fat, with a larger proportion of fat (B80% before and after peak bone mass is attained, is due to the direct fat).15,18 At birth nearly all the marrow is red. In the young adult, effect of regulated processes on mature bone cells associated with red marrow is found predominantly in the vertebrae, skull, bone formation (osteoblasts) and/or bone resorption (osteoclasts) sternum, ribs, skull pelvis and the proximal ends of femurs and which occur simultaneously during the lifespan. humerii, and in several of these bones (for example, vertebrae, A distinctly different hypothesis is that metabolic processes in sternum and ileum) red marrow continues to be replaced by mature fat cells influence the function of mature bone cells yellow marrow during the remaining adult lifespan.15 Second, fat (osteoblasts and/or osteoclasts) or vice versa. The location of bone fills the space made available from the net loss of bone mineral, fat in the trabercular area where remodelling is active raises the predominantly after the age of 40 years as part of the ‘aging’ possibility of a functional metabolic relationships between the two process. As a result of both of these processes, the amount of types of cells, including the provision of energy by fat cells to bone marrow fat during the adult lifespan doubles in both males allow osteoblasts and osteoclasts to remodel bone.27 The and females. In the reference 70 kg male there is 1.5 kg of red possibility of cross-talk between fat and bone cells is suggested Editorial 980 by the presence of receptors for fatty acids28 and adipokines, such mesenchymal cells towards the adipocyte cell line (more fat) at as leptin and adiponectin,29 on both osteoblasts and osteoclasts. the expense of osteoblast formation (less bone mass)).36,37 Much Two types of interactions have been suggested: systemic more needs to be understood about the underlying mechanisms and local.30 Experimental studies indicate that bone marrow fat controlling bone mass and function before novel pharmacological cells can inhibit the function and survival of osteoblasts while strategies to treat or prevent osteoporosis can be successfully stimulating osteoclast differentiation and function. This local or implemented in clinical practice. paracrine interaction depends on locally produced fatty acids and adipokines. The notion of systemic interactions is partly based on the potential activation of the same bone cell receptors by METHODOLOGICAL ISSUES circulating fatty acids and adipokines produced by extra-osseous Methodological issues associated with establishing bone adipose adipose tissue. It is also partly based on a variety of other tissue (or fat)-mineral relationships also need consideration since observations, such as the effect of hyperlipidemia in promoting they have more general implications for biomedical research. First, osteoclastic potential of mouse bone marrow cells examined in assessing BMD using DXA at least two potential errors can arise ex vivo,31 and on the effect of an atherogenic high fat diet in from the presence of fat. One relates to the inhomogeneous mice32 in reducing vertebral bone mineralisation, a process that distribution of fat around the projected bone (it is assumed that appears to involve reduced marrow expression of osteocalcin the fat in front and behind bone is similar to that in the other derived from osteoclasts. A relationship has also been reported areas surrounding the bone). The other relates to the presence of between visceral adipose tissue mass and fat in the lumbar intra-osseous fat. With an assumed variability (s.d.) of ±10% for vertebrae of humans19 although in the study of Shen et al. the the proportion of fat in lumbar vertebrae it was estimated,38 using relationship between volume of bone marrow fat and BMD data from three studies, that this would translate to an error in persisted after adjustment for visceral adipose tissue volume BMD estimation of ±0.4% (s.d.) to ±3%.38–40 Since the variability which was measured by MRI. in BMD in the study of Shen et al. is much greater than this (about Yet another theoretical possibility that may help explain the 15% when s.d. is expressed as a percentage of the mean BMD) inverse bone adipose tissue (or fat)-mineral relationship concerns the error arising from the presence of intra-osseous fat is likely to the effects of other systemic factors, such as circulating hormones be small. that simultaneously influence bone cells and intra-osseous fat Second, since DXA scanning is a two-dimensional process the cells. For example, a recent study19 found an inverse relationship amount of bone mineral is expressed in relation to a projected between fat in the lumbar vertebrae of humans, measured by bone area (areal density (areal BMD); g/cm2), from which the total magnetic resonance spectroscopy (MRS) (see below) and mineral content (BMC) of the bone or region of interest can be circulating insulin-like growth factor 1 concentration, which calculated (BMC ¼ areal BMD Â bone projected area). Some persisted after adjusting for age and body mass index. Studies studies have chosen to use only areal BMD8,11,13 to report their in mice found that low insulin-like growth factor 1 is associated results, as in the study of Shen et al.,1 while others use both areal with reduced bone size and trabercular bone density, reduced BMD and BMC.3,9,12 In many adult studies there is concordance expression of transcription factors involved in osteoblast between BMD and BMC, but this is not always the case. The differentiation, and an increase in bone marrow fat.33 Further- following examples are used to illustrate how discordance more, since there is insulin signalling in bone cells, it would be between areal BMD and BMC can influence the study findings interesting to explore the intriguing possibility of insulin resistance and/or conclusions. One study reported that 99% of peak BMD of in bone metabolism and whether this parallels insulin resistance in the spine occurred at 23 years whereas peak BMC probably intra- and extra-osseous adipose tissue. Irrespective of the occurred after 32 years,9 another study41 reported peak BMD at mechanisms involved there is growing evidence that bone the femoral neck of Hispanics at 20 years and BMC at 29 years, and marrow adipose tissue is linked to systemic influences and yet another study2 involving young American women, 99% of the systemic energy metabolism.29 The molecular biology of the peak whole body BMD was established by age 22 and BMC by age signalling processes, which is rapidly evolving, suggests that many 26 years. In a longitudinal Canadian study,10 changes in BMC and factors are involved in complex interactive processes. Since BMD occurred in parallel but there was some discordance in the human osteoclasts are continuously turning over there is the ranking order of different geographic regions, according possibility of modulating their turnover34 (osteoblast lifespan to whether peak BMD and BMC was used as the reference 10–15 days compared with B90 days for osteoblasts)34 and there indicator. A noteworthy example of discordance concerns a is also the possibility of cross-talk between these cells, which are systematic review with meta-analysis which found that birth derived from the haemopoietic rather than the mesangial cell weight had a highly significant effect on total BMC in the adult lines, and the haemopoietic cells in red marrow that produce (larger newly born babies end up with more total bone mineral) blood cells. While there is little information on these issues, but not on BMD.42 This difference can at least be partly explained there is clear evidence that interactions occur between yellow and by the greater adult height (implying longer and thicker bones) in red marrow. Substantial blood loss or the development individuals with higher birth weight, which has been haemolytic anaemia in adult life can lead to rapid replacement demonstrated consistently in cohort studies of this type. An of yellow marrow with red marrow, reducing the total fat content increase in height is usually associated with a much greater of marrow and altering bone adipose tissue (or fat)-mineral increase in BMC than in areal BMD,43–45 which is not surprising relationships. since total BMC depends not only on the extra mineral associated Understanding the mechanisms of cross-talk or communication with slightly thicker bones (reflected by an increase in areal BMD between different types of cells in bone may not only help explain and increased bone width) but also by the increase in bone the inverse bone adipose tissue (or fat)-mineral relationships but length. Particularly, short individuals are expected to have reduced also identify strategies for preventing and treating osteoporosis. areal BMD (less depth for X-rays to penetrate) and reduced A recent randomised placebo-control study in humans involving T scores, but not necessarily reduced volumetric bone density, the drug rosiglitazone,35 which activates peroxisome proliferator- which appears to show little variation with height. activated receptor-g, has surprisingly reported a tendency for both Third, the method of measuring fat or adipose tissue (not all of BMD (measured by DXA) and bone fat (by MRS) to decrease. which is fat) and the method of quantifying it can also influence Changes in opposite directions might have been expected (since the strength of bone adipose tissue (or fat)-mineral relationships laboratory studies have shown that activation of peroxisome and potentially the conclusions that emerge. The volume proliferator-activated receptor-g directs differentiation of of adipose tissue in a selected space or region of interest can

European Journal of Clinical Nutrition (2012) 979 – 982 & 2012 Macmillan Publishers Limited Editorial 981 be measured by MRI or computed tomography and expressed as mechanisms and the biological processes that determine bone the entire amount (ml) present in that space, the amount present structure and function. per unit volume, and even the amount per unit projected area when this is established by DXA. Relationships with other variables such as BMD or BMC may also vary. In the study of Shen et al., the CONFLICT OF INTEREST total volume of pelvic adipose tissue was measured semi- The author declares no conflict of interest. quantitatively by MRI and related to areal BMD. In contrast to MRI which measures adipose tissue volume in regions of interest, M Elia1,2 MRS obtains signals from fat and water in cuboidal areas of tissues 1Institute of Human Nutrition, University of Southampton, (rather than from the whole tissue or region of interest), and fat is Southampton, UK and expressed as a proportion of the fat plus water volume (rather 2Academic Unit: Human Development and Health, Faculty of than as a proportion of the total volume of the tissue or region of Medicine, University of Southampton, Southampton, UK interest), leaving some uncertainty as to whether fat þ water E-mail: [email protected] account for a large or small proportion of the total bone volume. Given that a variety of methods and indices have been used to describe the amount of fat and mineral in bone, it is not surprising REFERENCES that many different combinations of these have been used to examine bone adipose tissue (or fat) mineral relationships, among 1 Shen W, Chen J, Gantz M, Punyanitya M, Heymsfield SB, Gallagher D et al. them being the following: fat (ml or L)–BMD,23 as in the study of MRI-measured pelvic bone marrow adipose tissue is inversely related to DXA-measured bone mineral in younger and older adults. Eur J Clin Nutr 2012; Shen et al.1; fat/fat þ water–areal BMD,20,21 fat/water–areal 19,46 e-pub ahead of print 11 April 2012; doi:10.1038/ejcn.2012.35. BMD, fat/fat þ water–cortical bone (ml) and adipose tissue 2 Teegarden D, Proulx WR, Martin BR, Zhao J, McCabe GP, Lyle RM et al. Peak bone 16 volume fraction/total volume fraction. Care should be taken not mass in young women. 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European Journal of Clinical Nutrition (2012) 979 – 982 & 2012 Macmillan Publishers Limited